Evidence against a role for NLRP3-driven islet inflammation in db/db mice

H. L. Kammoun*, T. L. Allen, D. C. Henstridge, S. Barre, R. C. Coll, G. I. Lancaster, L. Cron, S. Reibe, J. Y. Chan, M. Bensellam, D. R. Laybutt, M. S. Butler, A. A.B. Robertson, L. A. O'Neill, M. A. Cooper, M. A. Febbraio

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Objectives: Type 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1β (IL-1β) have been implicated in pancreatic β cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic β cell death could allow for selective T2D treatment without compromising all IL-1β-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic β cell death, thereby preventing the onset of T2D. Methods: Diabetic db/db mice were treated with MCC950 via drinking water for 8 weeks from 6 to 14 weeks of age, a period over which they developed pancreatic β cell failure. We assessed metabolic parameters such as body composition, glucose tolerance, or insulin secretion over the course of the intervention. Results: MCC950 was a potent inhibitor of NLRP3-induced IL-1β in vitro and was detected at high levels in the plasma of treated db/db mice. Treatment of pre-diabetic db/db mice with MCC950, however, did not prevent pancreatic dysfunction and full onset of the T2D pathology. When examining the NLRP3 pathway in the pancreas of db/db mice, we could not detect an activation of this pathway nor increased levels of its target IL-1β. Conclusions: NLRP3 driven-pancreatic IL-1β inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D.

Original languageEnglish
Pages (from-to)66-73
Number of pages8
JournalMolecular Metabolism
Volume10
DOIs
Publication statusPublished - 01 Apr 2018
Externally publishedYes

Keywords

  • db/db mice
  • Inflammasome
  • Interleukin-1β
  • MCC950
  • Type 2 diabetes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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